(19) TZZ ¥_ _T (11) EP 2 443 125 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 491/14 (2006.01) C07D 491/22 (2006.01) 26.11.2014 Bulletin 2014/48 A61P 35/00 (2006.01) A61K 31/4741 (2006.01) (21) Application number: 10790151.4 (86) International application number: PCT/US2010/038890 (22) Date of filing: 16.06.2010 (87) International publication number: WO 2010/148138 (23.12.2010 Gazette 2010/51) (54) CAMPTOTHECIN DERIVATIVES CAMPTOTHECIN-DERIVATE DÉRIVÉS DE LA CAMPTOTHÉCINE (84) Designated Contracting States: • CAO: "Preparationof 14- nitrocamptothecin...", J. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB CHEM.SOC., PERKIN TRANS. 1, vol. 21, 1996, GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO pages 2629-2632, XP002684965, PL PT RO SE SI SK SM TR • CHENG KEJUN ET AL: "14-azacamptothecin: a potent water-soluble topoisomerase I poison.", (30) Priority: 17.06.2009 US 218043 P JOURNAL OF THE AMERICAN CHEMICAL 16.04.2010 US 325223 P SOCIETY 26 JAN 2005 LNKD- PUBMED: 15656613, vol. 127, no. 3, 26 January 2005 (43) Date of publication of application: (2005-01-26), pages838-839, XP002684966, ISSN: 25.04.2012 Bulletin 2012/17 0002-7863 • VADWAI VIRAL ET AL: "Insilico analysis of (73) Proprietor: Threshold Pharmaceuticals, Inc. homocamptothecin (hCPT) analogues for anti- Redwood City, California 94063 (US) tumour activity", INTERNATIONAL JOURNAL OF BIOINFORMATICS RESEARCH AND (72) Inventors: APPLICATIONS, INDERSCIENCE PUBLISHERS, • CAI, Xiaohong BUCKS, GB, vol. 5, no. 6, 1 January 2009 Redwood City, CA 94063 (US) (2009-01-01) , pages 603-615, XP009163526, • DUAN, Jian-Xin ISSN: 1744-5485 Redwood City, CA 94063 (US) • SAWADA S ET AL: "SYNTHESIS AND • MATTEUCCI, Mark ANTITUMOR ACTIVITY OF 20 Redwood City, CA 94063 (US) (S)-CAMPTOTHECIN DERIVATIVES: A-RING • CAO, Yeyu MODIFIED AND 7,10-DISUBSTITUTED Redwood City, CA 94063 (US) CAMPTOTHECINS", CHEMICAL & • JIAO, Hailong PHARMACEUTICAL BULLETIN, Redwood City, CA 94063 (US) PHARMACEUTICALSOCIETY OF JAPAN, JP, vol. 39, no. 12, 1 December 1991 (1991-12-01), pages (74) Representative: Wibbelmann, Jobst 3183-3188, XP008052765, ISSN: 0009-2363 Wuesthoff & Wuesthoff • VERMA RAJESHWAR P ET AL: "Camptothecins: Patent- und Rechtsanwälte a SAR/QSAR study.", CHEMICAL REVIEWS JAN Schweigerstrasse 2 2009 LNKD- PUBMED:19099450, vol. 109, no. 1, 81541 München (DE) January 2009 (2009-01), pages 213-235, XP002684967, ISSN: 1520-6890 (56) References cited: WO-A1-94/11376 US-A- 5 459 269 US-A1- 2007 093 432 US-B1- 6 403 604 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 443 125 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 443 125 B1 • DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 6 June2008 (2008-06-06), XP002684968, retrieved from STN Database accession no. 1026010-90-1 • FERRER S ET AL: "Studies on the reductively triggered release of heterocyclic and steroid drugs from 5-nitrothien-2-ylmethyl prodrugs", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 59, no. 19, 5 May 2003 (2003-05-05), pages 3437-3444, XP004421783, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(03)00481-2 2 EP 2 443 125 B1 Description [0001] The invention is limited to the subject-matter defined in the claims; the following specification is subject to this limitation. 5 FIELD OF THE INVENTION [0002] The present invention provides compounds useful in the treatment of cancer and other hyperproliferative dis- eases, and so relates to the fields of chemistry, biology, medicinal chemistry, pharmacology, and niedicine. 10 BACKGROUND OF THE INVENTION [0003] Camptothecin is a cytotoxin that inhibits topoisomerase I, an enzyme essential for DNA synthesis, and was first isolated from the leaves of the Camptotheca acuminata tree. Camptothecin showed anti-cancer activity in clinical 15 trials but was poorly soluble and generated adverse drug reactions. Topotecan (Hycamtin, GlaxoSmithKline) and iri- notecan (Campto, Yakult Honsha, and Camptosar, Pfizer) are semisynthetic derivatives of camptothecin, with the former approved by the U.S. FDA for the treatment of ovarian, cervical, and small cell lung cancer, and the latter approved for the treatment of colon cancer. Irinotecan is activated by hydrolysis to SN-38. The structures of these compounds are shown below along with the numbering used herein for the camptothecin ring. 20 25 30 35 Camptothecin: R1a = R1b = R2 = H; Topotecan: R1a = -CH2NMe2, R1b = OH, and R2 = H; Irinotecan: R1a = H, 40 45 and R2 = Et; and SN-38: R1a = H, R1b = OH, R2 = Et. [0004] The camptothecin derivatives approved for anti-cancer use are susceptible to one or more of the several mechanisms by which cancer cells can become resistant to chemotherapy. There remains a need for new camptothecin derivatives, particularly derivatives that are more potent anti-cancer agents, can be used to treat cancers resistant to treatment with the approved derivatives, and/or exhibit fewer or less severe adverse side effects. The present invention 50 meets this need. SUMMARY OF THE INVENTION [0005] In one aspect, the present invention provides compounds of Formula I: 55 3 EP 2 443 125 B1 5 10 15 wherein u is 0 or 1; R1a, R1b, and R1c each independently are H, halogen, hydroxyl, nitrile, amino, substituted amino, nitro, carboxyl ester, aminocarbonyl, substituted sulfonyl, aminosulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or 20 unsubstituted C 2-C6 alkynyl, substituted or unsubstituted C 2-C6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted C1-C6 alkoxy group, or R1a and R1b together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle, or R1b and R1c together with the carbon atoms to which they are bonded form a 5-7 membered heterocycle; 25 R2 is H, halogen, nitrile, formyl, oxime, hydrazone, imine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl group; or R2 and R1a together with the carbon atoms to which they are attached form a 5-7 membered substituted cycloalkyl ring; X is nitro or -NR3R4; 30 R3 and R4 each independently are H, C1-C6 alkyl, -CO2R5, or -COR6; R5 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 35 or an ester or salt, including a pharmaceutically acceptable salt, thereof, provided however that the compound excludes 14-nitro-20-acetoxycamptothecin. [0006] In another aspect, the present invention provides compounds prepared by the process comprising, consisting essentially, or consisting of contacting a compound of Formula IX or a salt or ester thereof: 40 45 50 55 wherein u, R1a, R1b, R2 are as defined in Formula I above, with fuming nitric acid, provided however that the compound prepared excludes 14-nitro-20-acetoxycamptothecin. [0007] In another aspect, the present invention provides methods for synthesizing the compounds of the present invention comprising, consisting essentially, or consisting of contacting a compound of Formula IX as shown above, or 4 EP 2 443 125 B1 a salt or ester thereof, wherein u R1a, R1b, R2 are as defined in Formula I above, with fuming nitric acid to provide a compound of Formula IXA: 5 10 15 [0008] In one embodiment of this method, the compound synthesized is a compound of Formula IXA in which u is 0. 20 In another embodiment, the contacting with nitric acid is performed in acetic anhydride. [0009] In another aspect, the present invention provides pharmaceutical compositions comprising, consisting essen- tially, or consisting of a compound of the present invention or 14-nitro-20-acetoxycamptothecin or a salt of either, and a pharmaceutically acceptable carrier, excipient, or diluent. [0010] In another aspect, the present invention provides a method of inhibiting growth of a cancer cell or another 25 hyperproliferative cell comprising, consisting essentially, or consisting of contacting the cancer cell with an effective amount of a compound of the present invention, 14-nitro-20-acetoxycamptothecin, or a salt of either, or with a pharma- ceutical composition of the present invention. [0011] In another aspect, the present invention provides a method of treating cancer or another hyperproliferative disease comprising, consisting essentially, or consisting of administering a therapeutically effective amount of a com- 30 pound of the present invention, 14-nitro-20-acetoxycamptothecin, or a salt of either, or administering a pharmaceutical composition of the present invention to a patient in need of such treatment, thereby treating the cancer or other hyper- proliferative disease. [0012] In another aspect, the present invention provides a use of a compound of the present invention, 14-nitro-20- acetoxycamptothecin, or a salt of either for the manufacture of a medicament for the treatment of cancer or another 35 hyperproliferative disease. DETAILED DESCRIPTION OF THE INVENTION Definitions 40 [0013] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments and/or aspects only and is not intended to limit the scope of this invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the meanings below.